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Mapping Subpopulations of Cancer Cell-Derived Extracellular Vesicles and Particles by Nano-Flow Cytometry

  • Dongsic Choi
    Dongsic Choi
    Research Institute of the McGill University Health Centre, Glen Site, McGill University, Montreal, Quebec H4A 3J1, Canada
    More by Dongsic Choi
  • , 
  • Laura Montermini
    Laura Montermini
    Research Institute of the McGill University Health Centre, Glen Site, McGill University, Montreal, Quebec H4A 3J1, Canada
    More by Laura Montermini
  • , 
  • Hyeonju Jeong
    Hyeonju Jeong
    Research Institute of the McGill University Health Centre, Glen Site, McGill University, Montreal, Quebec H4A 3J1, Canada
    More by Hyeonju Jeong
  • , 
  • Shivani Sharma
    Shivani Sharma
    Department of Pathology & Laboratory Medicine and California Nanosystems Institute, University of California at Los Angeles, Los Angeles, California 90095, United States
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  • , 
  • Brian Meehan
    Brian Meehan
    Research Institute of the McGill University Health Centre, Glen Site, McGill University, Montreal, Quebec H4A 3J1, Canada
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  • , and 
  • Janusz Rak*
    Janusz Rak
    Research Institute of the McGill University Health Centre, Glen Site, McGill University, Montreal, Quebec H4A 3J1, Canada
    *E-mail: [email protected]
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    Orcidhttp://orcid.org/0000-0002-2912-5566
Cite this: ACS Nano 2019, 13, 9, 10499–10511
Publication Date (Web):August 30, 2019
https://doi.org/10.1021/acsnano.9b04480
Copyright © 2019 American Chemical Society
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    Abstract

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    The elusive complexity of membranous extracellular vesicle (EV) and membrane-less extracellular particle (EP) populations released from various cellular sources contains clues as to their biological functions and diagnostic utility. In this study, we employed optimized multicolor nano-flow cytometry, structured illumination (SIM), and atomic force microscopy (AFM) to bridge sensitive detection at the single EV/EP level and high-throughput analysis of cancer cell secretomes. We applied these approaches to particles released from intact cells driven by several different transforming mechanisms or to cells under therapeutic stress imposed by pharmacological inhibition of their oncogenic drivers, such as epidermal growth factor receptor (EGFR). We demonstrate a highly heterogeneous distribution of biologically relevant elements of the EV/EP cargo, including oncoproteins (EGFR), clotting factors (tissue factor), pro-metastatic integrins (ITGA6, ITGA4), tetraspanins (CD63), and genomic DNA across the entire particulate secretome of cancer cells. We observed that targeting EGFR activity with irreversible kinase inhibitors (dacomitinib) triggers emission of DNA containing EP/EV subpopulations, including particles (chromatimeres) harboring both EGFR and DNase-resistant chromatin. While nano-flow cytometry enables quantification of these changes across the entire particular secretome, SIM reveals individual molecular topography of EV/EP subsets and AFM exposes some of their physical properties, including the presence of nanofilaments and other substructures. We describe differential uptake rates of distinct EV subsets, resulting in preferential internalization of exosome-like small EVs by cancer cells to the exclusion of larger EVs. Thus, our study illustrates the potential of nano-flow cytometry coupled with high-resolution microscopy to explore the cancer-related EV/EP landscape.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsnano.9b04480.

    • Supplementary Figures S1–S17 and extended methods contain additional control, quantification, and imaging experiments that strengthen the content of the manuscript (PDF)

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